Updates in ANCA-associated vasculitis

Abstract

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) are small-vessel vasculitides that include granulomatosis with polyangiitis (formerly Wegener's granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (Churg - Strauss syndrome). Renal-limited AAV can be considered a fourth entity. Despite their rarity and still unknown cause(s), research into AAV has been very active over the past decades and has allowed for the development of new therapeutic regimens. The pathogenesis is a complex process of immune dysregulations with genetic and environmental influences. Recent genome-wide association studies have identified multiple genetic predisposing variants, especially at the major histocompatibility complex region. The pathogenic role of antimyeloperoxidase ANCA (MPO-ANCA) is well supported by several animal models, but that of antiproteinase 3 ANCA (PR3-ANCA) is not as strongly demonstrated. B cells likely play a major role in the pathogenesis because they produce ANCAs, as do neutrophil abnormalities, imbalances in T-cell subtypes, and/or cytokine - chemokine networks. The role of the alternative complement pathway was established more recently, and studies of the antagonist of human C5a receptor (avacopan) in AAV have just been completed, with promising results. The current standard management of severe AAV still consists of remission induction therapy with glucocorticoids combined with rituximab or, less often now, cyclophosphamide. Several studies showed that reduced-dose regimens of glucocorticoids are noninferior to the previously used heavier regimens, for therefore less cumulative exposure to glucocorticoids. Avacopan use may even lead to new steroid-free therapeutic approaches, at least for some selected patients. Several trials and studies have now shown the superiority of rituximab over azathioprine or methotrexate as maintenance therapy. However, the optimal dosing regimen and duration for maintenance remain to be better defined, at the individual patient level. Many changes have occurred in the standard of care for AAV over the past decades, and more are expected soon, including with use of avacopan, but also, likely, a few other agents under investigation or development.

Figure 1.

Saddle-nose deformity in a patient with granulomatosis with polyangiitis ( GPA ).

Figure 2.

Nasal septum perforation in a patient with GPA. Note the light going from one nostril to the other through the perforated nasal septum and the crusty bleeding posterior wall of the sinonasal cavity.

Figure 3.

Purpuro-ecchymotic skin lesions on the legs of a patient with eosinophilic granulomatosis with polyangiitis (EGPA). Legs are the most involved areas for skin lesions in antineutrophil cytoplasm antibody (ANCA)associated vasculitides.

Figure 4.

Nodular cutaneous lesions in a patient with GPA. Elbows are a frequent location for such skin lesions in GPA and EGPA.

Figure 5.

Computed tomography (CT) scan of sinuses in a patient with GPA. Note the perforated nasal septum and bilateral opacification of maxillary sinuses - sinusitis.

Figure 6.

Chest CT of a patient with GPA. Note the multiple solid lung nodules, surrounded by ground-glass opacities, suggestive of associated peri-nodular alveolar hemorrhage.

Figure 7.

Chest CT in a patient with microscopic polyangiitis (MPA). Note the diffuse ground-glass opacities, suggestive of alveolar hemorrhage, with some pseudonodular consolidation appearance in the left lung.

Figure 8.

Histology of muscle-nerve biopsy in a patient with EGPA. Note the massive vessel wall and peri-vascular infiltrate by inflammatory cells, mainly eosinophils, the vessel wall necrosis and subsequent vessel lumen occlusion.